Abstract Aims To define risk factors associated with mother-to-child transmission (MTCT) and to create supporting evidence for the National Hepatitis B Perinatal Prevention Program (HBPPP) in Korea. Methods We analyzed HBPPP mother-infant pair data enrolled from 2002 to 2021. The major outcome was the HBsAg status of the infant resulting from post-vaccination serological testing. Additionally, we used prescription records of antivirals against the hepatitis B virus (telbivudine, tenofovir disoproxil fumarate) from 2010 to 2021 by data linkage with the National Health Insurance claims data. To select significant risk factors by maternal HBeAg status based on the data from 34 to 42 weeks of pregnancy, multivariate logistic regression analysis was used. Results Data from 232,242 mother-infant pairs were analyzed. Among 154,331 (66.5%) infants with post-vaccination serological testing results, 3,620 (2.3%) were HBsAg-positive. The incidence of MTCT has shown a decreasing trend, from 4.1% in 2002 to 1.0% in 2021. However, the rate was high at 5.5% (1822/32986) for infants of HBeAg-positive mothers. Maternal antiviral prescription during the pregnancy period, old age, HBeAg negative, delivery type (C-section), and breastfeeding were significant factors in decreasing the risk of MTCT. Among the HBeAg-positive, there was a significant difference in the antiviral prescription 0.7% (11/1692) compared to the non-prescription 4.9% (789/16264) [aOR, 7.71; 95% CI, 4.24-14.02]. The result was similar for the HBeAg-negative group, 0.7% (302/44888). Conclusions To eradicate the hepatitis B virus on a national level, MTCT must be further reduced. To achieve this, it is necessary to introduce strong additional preventive measures, including quantitative HBV DNA testing for mothers with chronic hepatitis B and administering antiviral prophylaxis at the third trimester of pregnancy with HBV-DNA ≥200,000 IU/mL into the HBPPP. Key messages • The incidence of mother-to-child transmission has shown a decreasing trend, from 4.1% in 2002 to 1.0% in 2021. • Maternal antiviral prescription, old age, HBeAg negative, delivery type (C-section), and breastfeeding were significantly decrease the risk of mother-to-child transmission.